One of the primary manifestations of COVID-19 is respiratory disease.  ACE2 expression was assessed in human airway epithelial tissue to better understand how SARS-CoV-2 interacts. with these cells. Studies included:

- ACE2 expression in healthy nonsmokers
- ACE2 expression in smokers
- ACE2 expression modulation by air pollution
- ACE2 expression modulated by miRNA (miR-1246)
- ACE2 expression in basal cells from the large and small airway epithelia of healthy nonsmokers

ACE2 Expression in Human Airway Epithelial Tissue

According to the GEPIA dataset, nearly all cancer tissues can express ACE2 with renal cancer having the highest expression level.  Some cancerous tissues were found to have a significant increase in ACE2 when compared against the same noncancerous tissue.  

Cancer Tissue Expression of ACE2

Expression levels were determined using the HPA (https://www.proteinatlas.org).  Tissues that express ACE2 were broken down into five categories based off of the amount of ACE2 mRNA expression:

- (1, highest expression, score range: 122-10) small intestine, colon, duodenum, kidney, testis, gallbladder and heart muscle
- (2, medium high expression, score range: 5-1) adipose tissue, thyroid gland, epididymis, ductus deferens, breast, pancreas, rectum, ovary, esophagus, liver, seminal vesicle, salivary gland and placenta
- (3, medium low expression, score range: 0.9-0.5) vagina, lung, appendix, skeletal muscle, fallopian tube, lymph node, tongue, stomach and prostate
- (4, low expression, score range: 0.4-0.1) remaining tissues
- (5, no expression, score range: 0) parathyroid gland, bone marrow, monocytes, B-cells, NK-cells, dendritic cells and total peripheral blood mononuclear cell

ACE2 Protein and mRNA Expression in Tissue

ACE2 is known to be expressed in a variety of different tissues, including:

- Heart, kidneys, gastrointestinal (GI) tract, lungs, brain, testes, bladder, adipose tissue, vascular system, cholangiocytes (epithelial cells of the oral and nasal mucosa)

ACE2 expression may explain the SARS-CoV-2 organ localization.

Expression of ACE2 in Tissue and COVID-19

ACE2 expression was quantified in 21 regions of the human brain using multiple tissue expression (MTE) arrays (*p < 0.01 (ANOVA); error bars represent one standard deviation of the mean).  The highest expression was found in the pons, amygdala, and the medulla oblongata.  The pons and medulla oblongata are notably known to control breathing and respiration. 

ACE2 Expression in the Human Brain

- cancer tissue
- human airway epithelium tissue
- human brain expression
- protein and mRNA expression
- relationship to COVID-19

Michigan State University

- subcellular expression
- tissue and organ expression
- mediators that influence expression
- comparing to TMPRSS2 expression
- circulating expression
- expression in embryonic development

ACE2 Expression

Data from primary manuscripts and microscopy screenings were used to assign a confidence level to the likelihood of different subcellular locations expressing ACE2.  This study showed that the extracellular space and plasma membrane are the most likely places to express ACE2 (confidence = 5), and the Golgi apparatus is the least likely (confidence = 1) out of these listed locations.  

Subcellular Expression of ACE2

- drug mediators
- non-drug mediators
- genetic mediators
- disease states

Mediators that Infleunce ACE2 Expression

- comparing expression levels in different tissues
- comparing expression levels by sex
- coexpression of TMPRSS2 and ACE2 

Comparing TMPRSS2 and ACE2 Expression

- Increased Concentrations of Circulating ACE2 is Associated with Mild COVID-19 Symptoms 
- Circulating ACE2 expression compared to circulating ACE

Expression of Circulating ACE2 and COVID-19

Pregnant mice were used to assess the expression levels of the following genes associated with SARS-CoV-2, inflammation, and other viral diseases:

- ACE2: cellular receptor for the SARS-CoV-2 virus
- TMPRSS2: serine protease involved in cellular entry of the SARS-CoV-2 virus
- St3gal4: related to the influenza virus
- St6gal1: related to the influenza virus
- Ifngr1: related to inflammation
- Tnfrsf1a: related to inflammation

Mice were sacrificed at the following timepoints:

- E12.5: embryonic day 12 (gravid females are sacrificed)
- E14.5: embryonic day 14 (gravid females are sacrificed)
- P1: day pups are born (pups are sacrificed)

Epithelium (Epi) and mesenchyme (Mes) tissue were collected from the soft pallets (SP) and tongues (T) of the different developmental stages.  Notably, ACE2 expression was only observed in large quantities in P1 mice, and TMPRSS2 expression increased throughout the developmental process.  FPKM: fragments per kilobase million reads

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